Prolonged Particulate Hexavalent Chromium Exposure Suppresses Homologous Recombination Repair in Human Lung Cells
Prolonged Particulate Hexavalent Chromium Exposure Suppresses Homologous Recombination Repair in Human Lung Cells
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DOI：
10.1093/toxsci/kfw103
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发表时间：
2016-09-01
影响因子：
3.8
通讯作者：
Wise, John Pierce, Sr.
中科院分区：
文献类型：
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作者：
Browning, Cynthia L.;Qin, Qin;Wise, John Pierce, Sr.
基因组不稳定性是致癌作用的主要模型之一，也是几乎所有癌症的特征。同源重组（HR）修复通过在DNA双链断裂修复期间维持高基因组保真度来防止基因组不稳定性。HR修复的定义步骤是Rad 51核丝的形成，这有助于寻找同源序列和模板DNA链的侵入。颗粒六价铬（Cr（VI））是一种人类肺癌致癌物，可诱导DNA双链断裂和染色体不稳定。由于HR修复的损失增加了Cr（VI）诱导的染色体不稳定性，我们研究了延长Cr（VI）暴露对HR修复的影响。我们表明，急性（24小时）铬（VI）暴露诱导正常的HR修复反应。相反，延长（120小时）暴露于颗粒铬（VI）抑制HR修复和Rad 51核丝的形成。长时间的铬（VI）曝光Rad 51有深远的影响，证明了蛋白质水平降低和Rad 51错误定位到细胞质。Rad 51核进口和核丝形成的蛋白质的反应显示不同的反应，长期铬（VI）曝光。BRCA 2在长时间Cr（VI）暴露后形成核灶，而Rad 51 C灶的形成受到抑制。这些结果表明，颗粒铬（VI），一种主要的化学致癌物，抑制HR修复的目标Rad 51，导致DNA双链断裂修复的低保真度，Rad 51-独立的修复途径。这些结果进一步增强了我们对Cr（VI）诱导的染色体不稳定性的潜在机制的理解，从而致癌。
Genomic instability is one of the primary models of carcinogenesis and a feature of almost all cancers. Homologous recombination (HR) repair protects against genomic instability by maintaining high genomic fidelity during the repair of DNA double strand breaks. The defining step of HR repair is the formation of the Rad51 nucleofilament, which facilitates the search for a homologous sequence and invasion of the template DNA strand. Particulate hexavalent chromium (Cr(VI)), a human lung carcinogen, induces DNA double strand breaks and chromosome instability. Since the loss of HR repair increases Cr(VI)-induced chromosome instability, we investigated the effect of extended Cr(VI) exposure on HR repair. We show acute (24 h) Cr(VI) exposure induces a normal HR repair response. In contrast, prolonged (120 h) exposure to particulate Cr(VI) inhibited HR repair and Rad51 nucleofilament formation. Prolonged Cr(VI) exposure had a profound effect on Rad51, evidenced by reduced protein levels and Rad51 mislocalization to the cytoplasm. The response of proteins involved in Rad51 nuclear import and nucleofilament formation displayed varying responses to prolonged Cr(VI) exposure. BRCA2 formed nuclear foci after prolonged Cr(VI) exposure, while Rad51C foci formation was suppressed. These results suggest that particulate Cr(VI), a major chemical carcinogen, inhibits HR repair by targeting Rad51, causing DNA double strand breaks to be repaired by a low fidelity, Rad51-independent repair pathway. These results further enhance our understanding of the underlying mechanism of Cr(VI)-induced chromosome instability and thus, carcinogenesis.